This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Plummer, N. W. Articles by Marchuk, D. A. Search for Related Content PubMed PubMed Citation Articles by Plummer, N. W. Articles by Marchuk, D. A.

(American Journal of Pathology. 2004;165:1509-1518.)
© 2004 American Society for Investigative Pathology

Loss of p53 Sensitizes Mice with a Mutation in Ccm1 (KRIT1) to Development of Cerebral Vascular Malformations

Nicholas W. Plummer^*, Carol J. Gallione^*, Sudha Srinivasan^*, Jon S. Zawistowski^*, David N. Louis and Douglas A. Marchuk^*

From the Department of Molecular Genetics and Microbiology,^* Duke University Medical Center, Durham, North Carolina; and the Department of Pathology, Neurosurgical Service and Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

Cerebral cavernous malformations (CCM) consist of clusters of abnormally dilated blood vessels. Hemorrhaging of these lesions can cause seizures and lethal stroke. Three loci are associated with autosomal dominant CCM, and the causative genes have been identified for CCM1 and CCM2. We have generated mice with a targeted mutation of the Ccm1 gene, but an initial survey of 20 heterozygous mice failed to detect any cavernous malformations. To test the hypothesis that growth of cavernous malformations depends on somatic loss of heterozygosity at the Ccm1 locus, we bred animals that were heterozygous for the Ccm1 mutation and homozygous for loss of the tumor suppressor Trp53 (p53), which has been shown to increase the rate of somatic mutation. We observed vascular lesions in the brains of 55% of the double-mutant animals but none in littermates with other genotypes. Although the genetic evidence suggested somatic mutation of the wild-type Ccm1 allele, we were unable to demonstrate loss of heterozygosity by molecular methods. An alternative explanation is that p53 plays a direct role in formation of the vascular malformations. The striking similarity of the human and mouse lesions indicates that the Ccm1^+/– Trp53^–/– mice are an appropriate animal model of CCM.

This article has been cited by other articles:

				P. Brouillard and M. Vikkula Genetic causes of vascular malformations Hum. Mol. Genet., October 15, 2007; 16(R2): R140 - R149. [Abstract] [Full Text] [PDF]

				N Revencu and M Vikkula Cerebral cavernous malformation: new molecular and clinical insights J. Med. Genet., September 1, 2006; 43(9): 716 - 721. [Abstract] [Full Text] [PDF]

				M. E. Sughrue and E. S. Connolly Jr Possible Mechanistic Overlap Between Cavernous Malformations and Cerebral Developmental Venous Anomalies Stroke, November 1, 2005; 36(11): 2339 - 2339. [Full Text] [PDF]

				B. Guclu, A. K. Ozturk, K. L. Pricola, A. Seker, M. Ozek, and M. Gunel Cerebral Venous Malformations Have Distinct Genetic Origin From Cerebral Cavernous Malformations Stroke, November 1, 2005; 36(11): 2479 - 2480. [Abstract] [Full Text] [PDF]

				M. J. Alberts and E. Tournier-Lasserve Update on the Genetics of Stroke and Cerebrovascular Disease 2004 Stroke, February 1, 2005; 36(2): 179 - 181. [Full Text] [PDF]